Heterocyclic amines having central nervous system activity

ABSTRACT

Tricyclic nitrogen containing compounds, having anxiolytic and anti-depressant activity and central nervous system activity of the following structural formula: 
                         
and pharmaceutically acceptable salts thereof wherein R 1  and R 2  are independently hydrogen, C 1-6  alkyl or R 1  and R 2  are joined to form pyrrolidine, piperidine, morpholine or imidazole. X is OCH 3 , SO 2 R 3 , SO 2 CF 3  or CN where R 3  is C 1-6  alkyl or an Aryl; and Y is hydrogen, Cl, Br, F, CN, CONR 1 R 2 , CF 3 , OCH 3 , SO 2 NR 1 R 2 . These new compounds are suitable for treating anxiolytic disorder, schizophrenia, Parkinson&#39;s disease, anxiety, depression or as compounds for lowering blood pressure or treating migraine headaches in patients in need of such treatment.

The present application is a divisional of U.S. application Ser. No.10/117,634, filed Apr. 5, 2002, which is a divisional of U.S.application Ser. No. 09/313,534, filed May 13, 1999, now U.S. RE 38,452,which is a reissue of U.S. application Ser. No. 08/592,328, filed Jan.17, 1994, issued as U.S. Pat. No. 5,652,245 on Jul. 29, 1997, now U.S.Pat. No. RE 38,452, which is a national phase of Internationalapplication No. PCT/US94/06648, International filing date 17 Jun. 1994,which was a continuation in part of U.S. patent application Ser. No.08/097,608, filed Jul. 27, 1993, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is directed toward tricyclic nitrogen containingcompounds, heterocyclic amines, having anxiolytic and anti-depressantactivity. These new compounds are suitable for treating central nervoussystem disorders including schizophrenia, Parkinson's disease, anxietyor as compounds for lowering blood pressure or treating migraines.

A series of dihydrophenalenes, tricyclic amine substituted compounds,and related compounds having central nervous system activity weredescribed in PCT Int. Pub. No. WO87/04153 and in PCT Int. Pub. No.WO88/04292. A major difference between those compounds and the presentinvention is that the subject compounds have at least one nitrogen atomin the tricyclic ring structure which is shared by two of the ringstructures. Generally, the subject compounds have exhibited anxiolyticactivity and better oral bioavaiability.

Information Disclosure Statement

PCT Int. Pub. No. WO87/04153 and PCT Int. Pub. No. WO88/04292 eachdescribe tricyclic structures having central nervous system activity.

U.S. Pat. No. 4,110,339 discloses4-(di-n-propyl)amino-1,3,4,5-tetrahydrobenz(cd)indole compounds usefulas prolactin inhibitors and in the treatment of Parkinsonism. EuropeanPatent Application 153,083 and German Patent 3,346,573 disclose methoxysubstituted 4-(di-n-propyl)amino-1,3,4,5-tetrahydrobenz(cd)indolecompounds. These publications disclose nitrogen containing tricyclicring structures but the nitrogen is not shared by any of the rings.

Evans, D. D., Peters, D. J., J. Chem. Soc., Perkin Trans. 1, pp 285–88(1974) discloses nitrogen containing tricyclic ring structures where thenitrogen is shared by two ring structures but additionally includesother substituents not common to the subject compounds.

PCT Int. Pub. No. WO 90/15058 discloses compounds with thecharacteristic tricyclic nitrogen containing structure of the subjectinvention with the exception of the ring nitrogen “X” substituents.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed toward tricyclicnitrogen containing compounds of Formula I:

and pharmaceutically acceptable salts thereof. R₁ and R₂ areindependently hydrogen, C₁₋₆ alkyl or R₁ and R₂ are joined to formpyrrolidine, piperidine, morpholine or imidazole. X is OCH₃, SO₂R₃,SO₂CF₃ or CN where R₃ is C₁₋₆ alkyl or an Aryl; and Y is hydrogen, Cl,Br, F, CN, CONR₁R₂, CF₃, OCH₃, SO₂NR₁R₂.

These new compounds have been found to exhibit anxiolytic activity inisolation induced aggression and plasma corticosterone models. They arealso suitable for treating various central nervous system disorderseffected by 5-HT_(1A) receptors such as, schizophrenia, Parkinson'sdisease, anxiety, depression, or as compounds for lowering bloodpressure and treating migraine headaches in patients in need of suchtreatments.

In yet another aspect, the present invention is a method for treatingcentral nervous system (CNS) disorders influenced by 5-HT_(1A) receptorssuch as anxiety, depression, hypertension and associated high bloodpressure, Parkinson's disease and schizophrenia in animal or human hostsby administering a pharmaceutically effective amount of a compound ofFormula I including pharmaceutically acceptable salts. Other uses forthese compounds include panic attacks, eating disorders,obsessive-compulsive disturbances seen in dementia disorders. Inaddition, central 5-HT receptor activation are believed to be involvedin mediating sexual behavior and therefore these compounds would beuseful to stimulate sexual activity and to alleviate impotence.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes compounds of Formula I, above, havingcentral nervous system activity. The compounds are characterized by atricyclic ring structure having a shared nitrogen atom between tworings, an amine substituent (NR₁R₂) and a substituted ring nitrogen (X)as structurally depicted by Formula I. The systematic names for the ringsystems in these compounds may be found by consulting the Ring SystemsHandbook, 1988 edition, published by Chemical Abstracts Service. Thesenames are derived by combining the names of benzene or a monocyclicheterocycle with the name of a bicyclic heterocycle to which it isfused. The atoms and bonds common to the fused rings are then specifiedto distinguish it from isomeric systems with similar names.

The particular compounds have been found to be active in various centralnervous system screens such as hypothermia and hypoxic stress tests andhave been found to be dopamine and serotonin such as, 5HT_(1A) receptorbinding assay antagonists.

The following definitions are applied to the structural formularepresented by Formula I, above.

“C₁–C₆ alkyl” means methyl, ethyl propyl butyl pentyl and hexyl andisomeric forms thereof.

“Aryl” means aromatic ring structures containing five to ten carbonatoms which can be optionally substituted with halogen atoms, C₁₋₆ alkyl(which can be optionally substituted with halogen and hydroxyl groups)and hydroxyl groups such as phenyl, α-naphthyl, β-naphthyl,m-methylphenyl p-trifluoromethylphenyl and the like. Aryl also includesthe various heteroaryl groups which contain the heteroatoms nitrogen,sulfur or oxygen to form pyridine, thiophene, furan, pyrimidine,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 3-pyridazinyl, 4-pryidazinyl, 3-pyrazinyl, 2-quinolyl,3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl,4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 2-imidazolyl,4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-indolyl, 3-indolyl,3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl,2-benzofuranyl, 3-benzofuranyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl,5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl,1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl.

“Pharmaceutically acceptable salts” are hydrochloride, hydrobromide,hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate,malate, succinate, tartrate, cyclohexanesulfamates, methanesulfonates,ethanesulfonates, benzenesulfonates, toluenesulfonates and otherpharmaceutically acceptable counter ions for amines. Additionally, thecompounds of this invention may be administered in a suitable hydratedform.

The compounds of the invention include both racemic and optically pureproducts which can be separated by conventional methods into the R- andS-isomers. Resolution can be accomplished using resolving agents such asoptically active dibenzoyltartaric acid, camphorsulfonic acid,bis-o-toluoyltartaric acid, tartaric acid, and diacetyl tartaric acid.

A second procedure useful in resolving primary and secondary aminecompounds of Formula I involves their conversion to diastereomericamides using an optically active acid. The diastereomeric amides areseparated and the amide bond is cleaved to afford the optically pureFormula I compounds. This procedure is illustrated in PCT InternationalPublication No. WO 90/15058 (Examples 49 and 50) for the preparation ofthe optical isomers using t-butoxycarbonyl-L-phenylalanine as theresolving agent. For the resolution, the racemic compound is coupled tot-butoxycarbonyl-L-phenylalanine and the diastereomeric amide productsare separated by chromatography into the (+) and (−) forms. The (−)isomer is reacted with trifluoracetic acid to give (−)N-(5,6-dihydro-2-oxo-4H-imidazo(4,5,1-ij)quinolin-5-yl)-L-phenylalanineamide. Edman degradation of this compound,by reaction with phenyl isothiocyanate followed by trifluoracetic acid,removes the phenylalanine residue and affords the (−) form of thecompound. Further reaction of this product with propionaldehyde andsodium cyanoborohydride gives the (−) form of the active isomer.

General procedures for preparing compounds of Formula I are shown inSchemes 1 and 2, below, and as cross-referenced and described in theExamples. Methods for preparing various intermediates for the subjectcompounds are described in PCT International Publication No. WO 90/15058herein incorporated by reference.

The dosage regimen for treating patients with the compounds of thisinvention is selected in accordance with a variety of factors includingthe type, age, weight, sex, and medical condition of the patient, theseverity of the psychosis, the route of administration and theparticular compound employed. An ordinarily skilled physician orpsychiatrist will readily determine and prescribe the effective amountof compound to prevent or arrest the progress of the condition. In soproceeding, the physician or psychiatrist could employ relatively lowdosages at first, subsequently increasing the dose until a maximumresponse is obtained.

Initial dosages of the compounds of the invention are ordinarily in thearea of at least 10 mg up to about 1200 mg per day orally, which may begiven in a single dose or in multiple doses. When other forms ofadministration are employed equivalent doses are administered. Whendosages beyond 600 mg are employed, care should be taken with eachsubsequent dose to monitor possible toxic effects.

The compounds of this invention are administered in oral unit dosageforms such as tablets, capsules, pills, powders, or granules. They mayalso be introduced parenterally, (e.g., subcutaneously, intravenously,or intramuscularly), using forms known to the pharmaceutical art. Theyalso may be administered rectally or vaginally in such forms assuppositories or bougies. In general the preferred route ofadministration is oral.

The compounds of this invention can also be administered aspharmaceutically or therapeutically acceptable salt such ashydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate,propionate, lactate, maleate, malate, succinate, tartrate,cyclohexanesulfamates, methanesulfonates, ethanesulfonates,benzenesulfonates, toluenesulfonates and the lie. Additionally, thecompounds of this invention may be administered in a suitable hydratedforum.

Compounds of the subject invention were evaluated in anisolation-induced aggression assay to measure their ability to controlor arrest aggressive behavior as measured against a saline “Control”.Male CF-1 mice (Charles River Labs) were housed singly in wire cagedrawers for several weeks of isolation and aggression training. Afterthis, the isolated mouse (weighing 30–50 g) initiated an “attack”whenever an intruder mouse was placed into his cage. Intruders were maleCF-1 Charles River mice, about the same size as isolated mice and housedin groups of 12 per cage. For drug testing, the isolated mice were dosedorally (p.o.) with drug or 0.25% methylceflulose vehicle. Thirty minuteslater, an intruder mouse was introduced and the latency to attack wasrecorded. Treatment groups (n=6), including a positive control, weretested by an observer blinded to the treatments, and there was anadditional non-blinded vehicle group. The results were as follows:

Compound Seconds Control 66 Example 1¹ 600 Control 152 Example 2² 565Control 66 Example 2³ 600 ¹Formula I where R₁ is hydrogen, R₂ is methyl,Y is hydrogen and X is —OCH₃ (R-enantiomer); ²Formula I where R₁ ismethyl, R₂ is methyl, Y is hydrogen and X is —OCH₃ (racemate); ³FormulaI where R₁ is methyl, R₂ is methyl, Y is hydrogen and X is —OCH₃(R-enantiomer).

Compounds of Example 4 (Formula I where R₁ and R₂ are propyl, Y ishydrogen and X is —OCH₃) were evaluated in an receptor binding assay(5HT Ligand) for calculation of IC₅₀ values and Ki (nM) values. Receptorbinding assays are well known tests for evaluating compounds foractivity as described in “Cloning and Pharmacological Characterizationof a Novel Human 5-hydroxy-1-tryptamine_(1D) Receptor Sub-Type”, Mol.Pharm., 42 439–44 (1992), herein incorporated by reference. The resultswere as follows:

Compounds Ex. 4 Receptor Ligand Ki (nM) Racemate 5-HT1DA-Clone 5HT 15.20″ 5-HT1DB-Clone 5HT 7.17 R-Enantiomer 5-HT1DA-Clone 5HT 38.00 ″5-HT1DB-Clone 5HT 58.00 ″ 5-HT1A-Clone DPAT 97 S-Enantiomer 5-HT1A-CloneDPAT 904

The above data shows that the racemate compound is selective for the5HT_(1DB) receptor and that the activity resides in the R-enantiomercompound.

EXAMPLE 1(R)-5-Methylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one(8a) Preparation of Methyl(R)-N-(1,2,3,4-tetrahydro-1-methoxy-2-oxo-3-quinolinyl)carbamate (2a)

A solution of methyl chloroformate (42.8 g, 0.453 mol) in chloroform (50ml) was added to a mixture of(R)-1,2,3,4-tetrahydro-1-methoxy-2-oxo-3-quinolinamine 1 (M. Kawase, T.Kitamura, Y. Kilugawa, J. Org. Chem., 54, 1989 3394–3403)(0.15 mol) andsodium bicarbonate (50.4 g, 0.600 mol) in chloroform (250 ml) and water(100 ml) over a period of 10 minutes at 0° C. The mixture was stirredovernight at room temperature, diluted with pentane, and the layers wereseparated. The aqueous layer was extracted with diethylether, and thecombined organic extracts were washed with brine and dried (MgSO₄). Thesolvent was removed under vacuum to leave an amber oil. Purification byflash chromatography (230–400 mesh silica gel, 35–40% ethyl acetate inhexane) gave the title compound as a light yellow oil (37.0 g, 99%).

NMR (CDCl₃, TMS) δ2.865 (t, j=14.7 Hz, 1H), 3.437 (dd, j=6.0 & 15.3 Hz,1H), 3.723 (s, 3H, NOCH₃), 3.932 (s, 3H, COOCH₃), 4.426 (dt, J=5.& &14.2 Hz, 1H, N—CH), 5.856 (br. s, 1H, NH), 7.098 (t of d, j=1.2 & 7.4Hz, 1H), 7.228 (m, 2H), 7.331 (t, j=7.7 Hz, 1H).

[α]_(D)=−47° (25° C., CHCl₃, c=0.9977).

Preparation of (R)-3-Methylamino-1,2,3,4-tetrahydroquinoline (3a)

A solution of(R)-N-(1,2,3,4-tetrahydro-1-methoxy-2-oxo-3-quinolinyl)carbamate (2a,36.25 g, 0.145 mol) in tetrahydrofuran (400 ml) was cooled in ice, andborane dimethylsulfide complex (10M, 73 ml, 0.73 mol) was added. The icebath was removed, and mixture slowly came to a vigorous reflux whichrequired cooling with an ice bath. When the reaction subsided, it washeated at reflux on the steam bath overnight. The mixture was cooled inice, and water (80 ml) and then 10% aqueous hydrochloric acid (70 ml)were added dropwise. The mixture (acidic by pH paper) was stirred atreflux on the steambath for 1.25 hr. The mixture was cooled in ice andbasified slowly with solid sodium hydroxide. The mixture was dilutedwith water and pentane, and the layers were separated. The aqueous wasextracted with diethylether, and the combined organic extracts weredried (MgSO₄). The solvent was removed under vacuum to leave an oil(23.96 g, 100%). A sample (1.3 g) was purified via gravitychromatography (70–230 mesh silica gel; 6% methanol 0.6% ammoniumhydroxide, chloroform) to give the title compound as a light yellow oil(0.84 g).

NMR (CDCl₃, TMS) δ1.529 (br. s, 1H, methylamine NH), 2.503 (s, 3H,N—CH₃), 2.62–2.71 (m, 1H), 2.93–3.14 (m, 3H), 3.394 (d of t, j=2.2 &10.9 Hz, 1H), 3.814 (br. s, 1H, NH), 6.483 (d, j=7.7 Hz, 1H), 6.624 (dof t, j=1.0 & 7.4 Hz, 1H), 6.95–6.98 (m, 2H).

The compound (0.83 g, 5.12 mmol) was dissolved in methanol and combinedwith a solution of trimethylsilyl chloride (0.54 g, 5.0 mmol) inmethanol, and the solvent was removed under vacuum. The residue wascrystallized from methanol/diethylether to give the hydrochloride saltof the title compound (3a) as light yellow-green crystals (0.56 g, m.p.193–195° C.).

[α]_(D)=+26° (25° C., CH₃OH, c=1.0232).

Preparation of(R)-N-Methyl-N-[3-((1-trifluormethylacetyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(4a)

A solution of (R)-3-Methylamino-1,2,3,4-tetrahydroquinoline (3 a, 21.32g, 0.131 mol) in tetrahydrofuran (200 ml) was cooled in ice, andtrifluoracetic anhydride (69.2 g, 0.329 mol) was added dropwise. Themixture was stirred at 0° C. for 1 hr and at room temperature for 2 hr.The mixture was again cooled in ice and water (150 ml) was added. Solidsodium bicarbonate was added portionwise until the evolution of gasceased. The mixture was extracted three times with diethylether, and thecombined organic extracts were washed with saturated sodium bicarbonateand brine. The solution was dried (MgSO₄), and the solvent was removedunder vacuum to leave a yellow oil (42.2 g). Purification by flashchromatography (230–400 mesh silica gel; 15% ethyl acetate in hexane)gave the title compound as a yellow oil (31.12 g, 67% yield).

[α]_(D)=+59° (25° C., CHCl₃, c=0.5495).

MR (CDCl₃, TMS) δ2.75–3.40 (m, 5H), 3.65–3.95 (m, 1H), 3.95–4.30 (m,1H), 4.572 (quintet, j=7.6 Hz, 0.3H), 4.921 (m, 0.7H), 7.15–7.45 (m,3.7H), 7.697 (m, 0.3H).

Preparation of(R)-3-Methylamino-1-trifluoromethylacetyl-1,2,3,4-tetrahydroquinoline(5a)

A solution of(R)-N-Methyl-N-[3-((1-trifluormethylacetyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(4a, 29.78 g, 84.1 mmol) in tetrahydrofuran (140 ml) was cooled in iceand a solution of potassium hydroxide (45.6% solution, 7.5 ml, 89.3mmol) in water (40 ml) was added. The mixture was stirred a 0° C. for 30minutes and at room temperature for 1 hour. The mixture was extractedtwice with diethylether. The combined organic extracts were washed withbrine and dried (MgSO₄). The solvent was removed under vacuum to leave ayellow oil (21.7 g, 100%). A sample (1.05 g) was purified via flashchromatography (230–400 mesh silica gel, 15% ethyl acetate in hexane)gave a yellow oil (0.90 g). Crystallization from ethyl acetate/hexanegave the title compound as a colorless solid (0.45 g, m.p. 68–69° C.).

NMR (CDCl₃, TMS) δ2.871–3.182 (m, 5H, N—CH₃ & Ar—CH₂), 3.33–3.449 (m,2H, N—CH₂), 3.890 (br. s, 1H, NH), 4.35–4.48 (m, 0.4H, N—CH),4.800–4.888 (m, 0.6H, N—CH), 6.553 (t, j=7.6 Hz, 1H), 6.660–6.735 (m,1H), 6.996–7.068 (m, 2H).

[α]_(D)=−29° (25° C., CHCl₃, c=0.9917).

Preparation of(R)-N-Methyl-N-[3-(1-(N-methoxyaminocarbonyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(6a)

A solution of phosgene (1.93M in toluene, 15.6 ml, 30.1 mmol) in drytetrahydrofuran (75 ml) was cooled in ice and a solution of(R)-3-Methylamino-1-trifluoromethylacetyl-1,2,3,4-tetrahydroquinoline(5a, 7.75 g, 30.0 mmol) and triethylamine (4.20 ml, 30.1 mmol) in drytetrahydrofuran (75 ml) was added dropwise. The mixture was stirred inan ice bath for 50 minutes, and methoxylamine hydrochloride (5.01 g,60.0 mmol) and triethylamine (8.40 ml, 60 mmol) were added. The mixturewas stirred at room temperature for 24 hours, diluted with diethylether,and washed with water, 10% hydrochloric acid, saturated sodiumbicarbonate solution, and brine. The solution was dried (MgSO₄), and thesolvent was removed under vacuum to leave a oil (8.85 g). Purificationby flash chromatography (230–400 mesh silica gel, 50% ethyl acetate inhexane) gave the title compound as a colorless oil (7.42 g, 75% yield).

NMR (CDCl₃, TMS) δ2.817–3.097 (m, 5H, N—CH₃ & Ar—CH₂), 3.66–4.035 (m,5H, N—CH₂ & O—CH₃), 4.38–4.863 (m, 1H, N—CH), 7.148–7.366 (m, 4H), 7.813& 7.829 (two s, 1H, NH).

[α]_(D)=+5° (25° C., CHCl₃, c=1.137).

Preparation of(R)-5-N-(N-Methyltrifluoromethylacetamido)-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(7a)

A solution of(R)-N-Methyl-N-[3-(1-(N-methoxyaminocarbonyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(6a, 6.61 g, 20.0 mmol) in chloroform (100 ml) was degassed with argonand bis(trifluoroacetoxy)iodobenzene (10.32 g, 24 mmol) was addedportionwise. The solution was stirred at reflux for 7 minutes. Thereaction mixture was cooled, diluted with pentane, and washed twice withsaturated sodium bicarbonate solution and once with brine. The solutionwas dried (MgSO₄), and the solvent was removed under vacuum to leave ared-brown oil (11.5 g). Purification by flash chromatography (230–400mesh silica gel; 35–40% ethyl acetate in hexane) gave an amber solid(4.74 g, 72% yield). Crystallization from ethyl acetate/hexane gave thetitle compound as off-white crystals (4.55 g, m.p. 148.5–150.5° C.).

NMR (CDCl₃, TMS) δ2.995–3.299 (m, 5H, N—CH₃ & Ar—CH₂), 3.724–3.839 (m,1H), 4.089 & 4.099 (two s, 3H, O—CH₃), 5.059–4.227 (m, 1H), 4.520(heptet, j=5.4 Hz, 0.3H), 4.931 (heptet, j=5.1 Hz, 0.7H), 6.900–7.121(m, 3H).

[α]_(D)=+38° (25° C., CHCl₃, c=1.0215).

Preparation of(R)-5-Methylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(8a)

Potassium carbonate (2.05 g, 14.8 mmol) was added to a solution of(R)-5-N-(N-methyltrifluoromethylacetamido)-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(7a, 3.75 g, 11.4 mmol) in methanol (75 ml). The mixture was stirred atreflux for 7 hours. The solvent was removed under vacuum, and theresidue was partitioned between diethylether and water(0.75 ml). Theaqueous solution was saturated with brine and extracted twice more withdiethylether. The combined organic extracts were dried (MgSO₄), and thesolvent was removed under vacuum to leave an oil. After standing forthree days, the aqueous developed a precipitate which was extractedtwice with 75% tetrahydrofuran in diethylether. The combined organicextracts were dried (MgSO₄), and the solvent was removed under vacuum toleave a brown semisolid. The combined samples were purified via flashchromatography (230–400 mesh silica gel, 70–80% tetrahydrofuran in ethylacetate to give the title compound as an amber oil (2.7 g, 100%).

NMR (CDCl₃, TMS) δ2.545 (s, 3H, N—CH₃), 2.781 (dd, j=7.4 & 16.1 Hz, 1H),3.071 (dd, j=4.0 & 16.0 Hz, 1H), 3.233 (heptet, j=3.8 Hz, 1H), 3.645(dd, 7.0 & 12.4 Hz, 1H), 4.045 (m, 1H), 4.088 (s, 3H, NOCH₃), 6.893 (d,j=7.4 Hz, 1H), 6.964 (d, j=7.1 Hz, 1H), 7.039 (t, j=7.7 Hz, 1H).

A sample (0.70 g) was dissolved in tetrahydrofuran, diluted with diethylether, and excess ethereal hydrochloric acid was added. The precipitatewas filtered, washed with diethylether, and crystallized frommethanol/diethylether to give the hydrochloride salt of the titlecompound (8a) as tan crystals (0.68 g, m.p. 196–197° C.).

[α]_(D)=−26° (25° C., CH₃OH, c=1.0139).

EXAMPLE 2(R)-5-Dimethylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(9a)

Following the procedure of Example 1, a solution of(R)-5-Methylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(8a, 1.88 g, 8.06 mmol) in methanol (40 ml) was stirred at roomtemperature, and 37% aqueous formaldehyde (2.40 ml, 32 mmol) and aceticacid (0.98 g, 16.2 mmol) were added. The mixture was cooled in ice, andsodium cyanoborohydride (1.15 g, 17.0 mmol) was added portionwise over a5 minute period. The mixture was stirred at 0° C. for 5 minutes and atroom temperature for 6 hours. The solvent was removed under vacuum, andthe residue was diluted with 10% sodium carbonate solution and extractedtwice with diethylether. The combined organic extracts were washed withbrine and dried (MgSO₄). The solvent was removed under vacuum to leavean amber oil (2.06 g). Purification by flash chromatography (230–400mesh silica gel, 65% tetrahydrofuran in ethyl acetate) gave the titlecompound as an amber oil (1.77 g, 89% yield).

NMR (CDCl₃, TMS) δ2.436 (s, 6H, N—CH₃), 2.853–3.068 (m, 3H), 3.525–3.596(m, 1H), 4.081 (s, 3H, O—CH₃), 4.188–4.243 (m, 1H), 6.890 (d, j=7.4 Hz,1H), 6.954 (d, j=7.1 Hz, 1H), 7.033 (t, j=7.6 Hz, 1H).

The compound was dissolved in diethylether and excess etherealhydrochloric acid was added. The precipitate was filtered, washed withether and crystallized from methanol/diethylether to give thehydrochloride salt of the title compound (9a) as yellow crystals (1.76g, 195° C.).

[α]_(D)=−19° (25° C., CH₃OH, c=1.0234).

EXAMPLE 3(R)-5-Propylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(8b) (R)-N-(1,2,3,4-Tetrahydro-1-methoxy-2-oxo-3-quinolinyl)propanamide(2b)

The amine (1, 33.51 g, 0.135 mol) was dissolved in propionic anhydride(78.2 g, 0.60 mol) while controlling the temperature with an ice bath.The mixture was stirred at room temperature for 5 hours, and water (100ml) was added, saturated NaHCO₃ (200 ml) was slowly added, and then 10%Na₂CO₃ was slowly added to neutralize the mixture to pH 7.5. The mixturewas extracted with diethylether, saturated with sodium chloride, andextracted again with diethylether and a mixture of diethylether andchloroform. The combined extracts were washed with 5% Na₂CO₃ and brine.The solution was dried (MgSO₄), and the solvent was removed under vacuumto leave an amber oil. Purification by flash chromatography (230–400mesh silica gel, 60% ethyl acetate in hexane) gave an oil. A sample wascrystallized from ethyl acetate/hexane to give the title compound (2b)as colorless crystals (m.p. 98°–99° C.).

[α]_(D)=−100° (25° C., CHCl₃, c=0.9698).

NMR (CDCl₃, TMS) δ1.206 (t, J=7.6 Hz, 3H, CO—C—CH₃), 2.343 (q, J=7.6 Hz,2H, COCH₂), 2.768 (t, J=14.7 Hz, 1H), 3.527 (dd, J=6.1 & 15.1 Hz, 1H),3.934 (s, 3H, O—CH₃), 4.614 (d of t, J=5.6 & 14.2 Hz, 1H, N—CH), 6.633br. d, J=4.5 Hz, 1H, NH), 7.099 (d of t, J=1.2 & 7.4 Hz, 1H), 7.230 (d,J=7.9 Hz, 2H), 7.327 (t, J=7.7 Hz, 1H).

Preparation of (R)-1,2,3,4-Tetrahydro-N-propyl-3-quinolinaminemonohydrochloride (3b)

Borane methyl sulfide (10M, 42.5 ml, 0.425 mol) was added to a solutionof (R)-N-(1,2,3,4-Tetrahydro-1-methoxy-2-oxo-3-quinolinyl)propanamide(2b, 21.29 g, 85.7 mmol) in tetrahydrofuran (250 ml) with stirring atroom temperature. The reaction was exothermic, and an ice bath was usedto control the reaction. The mixture was stirred at 0° C. for 30minutes, at room temperature overnight, and then at reflux for 4 hours.The mixture was cooled in ice, and water (50 ml) was carefully addeddropwise. When the addition was complete, 10% HCl was added dropwiseuntil the mixture was acidic by pH paper. The mixture was stirred atroom temperature for 1 hour and at reflux for 1 hour. The mixture waswashed with pentane and filtered. The filtrate was basified with 15%sodium hydroxide and extracted with diethylether. The aqueous layer wassaturated with sodium chloride and extracted twice with diethylether.The combined ether extracts were dried (MgSO₄), and the solvent wasremoved under vacuum to leave an oil (14.8 g, 91%). A sample (1.0 g) waspurified via gravity chromatography (70–230 mesh silica gel, 90 g; 3%methanol 0.3% NH₄OH, CHCl₃) to give the title compound as a colorlessoil.

NMR (CDCl₃, TMS) δ0.924 (t, J=7.4 Hz, 3H, CH₃), 1.518 (sextet, J=7.4 Hz,3H), 2.641–2.711 (m, 3H), 2.965 (dd, J=4.0 & 14.7 Hz, 1H), 3.048–3.131(m, 2H), 3.361–3.432 (m, 1H), 3.825 (br. s, 1H), 6.488 (d, J=7.9 Hz,1H), 6.626 (d of t, J=1.0 & 7.4 Hz, 1H), 6.951–7.002 (m, 2H).

The compound (0.85 g, 4.47 mmol) was combined with a solution oftrimethylsilyl chloride (0.57 ml 4.49 mmol) in methanol. The solvent wasremoved under vacuum to leave a solid, which was crystallized twice frommethanol/diethylether to give the hydrochloride salt of the titlecompound (3b) as off-white crystals (m.p. 185–192° C.).

[α]_(D)=+12° (CH₃OH, 25° C., c=0.8073).

NMR (CD₃OD, TMS) δ1.038 (t, J=7.4 Hz, 3H, CH₃), 1.705–1.833 (m, 2H,propyl N—C—CH₂), 2.986 (dd, J=5.5 & 17.2 Hz, 1H), 3.065–3.120 (m, 2H,N—CH₂), 3.265–3.342 (m, 1H), 3.436–3.572 (m, 2H), 3.734–3.800 (m, 1H),6.731–6.805 (m, 2H), 7.037–7.084 (m, 2H).

Preparation of(R)-N-Propyl-N-[3-((1-trifluormethylacetyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(4b)

A solution of (R)-1,2,3,4-tetrahydro-N-propyl-3-quinolinamine (3b, 14.73g, 77.4 mmol) in tetrahydrofuran (50 ml) was cooled in ice andtrifluoroacetic anhydride (40.6 g, 0.193 mol) was added dropwise. Whenthe addition was complete, the cold bath was removed, and the mixturewas stirred overnight at room temperature. Water (75 ml) was added, andsodium bicarbonate was added portionwise until the mixture was basic tolitmus. The mixture was extracted three times with diethylether, and thecombined extracts were washed with saturated sodium bicarbonate solutionand brine. The solution was dried (MgSO₄), and the solvent was removedunder vacuum to leave an amber oil (28.4 g). A sample (0.87 g) waspurified via flash chromatography (230–400 mesh silica gel, 5–6% ethylacetate in hexane) to give a colorless oil which was crystallized fromhexane to give the title compound (4b) as colorless crystals (0.61 g,m.p. 77–79° C.).

NMR (CDCl₃, TMS) δ0.897–0.985 (m, 3H, propyl CH₃), 1.706 (sextet, j=7.7Hz, 2H, propyl N—C—CH2), 2.85–3.69 (m, 4H), 3.69–4.38 (m, 2.6H), 4.500(quintet, 0.4H), 7.15–7.40 (m, 3.6H), 7.726 (br. s, 0.4H).

[α]_(D)=+8° (25° C., CHCl₃, c=1.0067).

Preparation of(R)-N-Propyl-N-[3-(1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(5b)

A solution ofN-Propyl-N-[3-((1-trifluormethylacetyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(4b, 27.64 g, 72.3 mmol) in tetrahydrofuran (200 ml) was cooled in ice,and a solution of potassium hydroxide (45.6% in water, 6.07 ml, 72.3mmol) was added. The mixture was stirred at 0° C. for 15 minutes and atroom temperature for 30 minutes. The mixture was diluted withdiethylether, and the layers were separated. The aqueous layer wasextracted with diethylether, and the combined organic extracts werewashed with brine and dried (MgSO₄). The solvent was removed undervacuum to leave an oil (21.4 g). Purification by flash chromatography(230–400 mesh silica gel; 10% ethyl acetate in hexane) gave a yellow oil(16.68 g, 81% yield). A sample (0.75 g) was rechromatographed using thesame conditions to give an oil which crystallized (0.66 g).Crystallization from hexane gave the title compound (5b) as colorlesscrystals (0.54 g; m.p. 68–69° C.).

NMR (CDCl₃, TMS) δ0.883–0.946 (m, 3H, propyl CH₃), 1.58–1.77 (m, 2H,propyl N—C—CH₂), 2.83–2.95 (m, 1H), 3.104–3.483 (m, 4.5H), 3.708 (t,j=10.4 Hz, 0.5H), 3.893 (br. s, NH), 4.16–4.28 & 4.32–4.46 (m, 1H,N—CH), 6.546 (t, j=6.9 Hz, 1H), 6.647–6.725 (m, 1H), 6.965–7.063 (m,2H).

[α]_(D)=−62° (25° C., CH₃OH, c=0.9991).

Preparation of(R)-N-Propyl-N-[3-(1-(N-methoxyaminocarbonyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(6b)

A solution of phosgene (1.93 M in toluene, 10.4 ml, 20.0 mmol) in drytetrahydrofuran (50 ml) was cooled in ice and a solution ofN-Propyl-N-[3-(1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(5b, 5.73 g, 20.0 mmol) and triethylamine (2.03 g, 20.1 mmol) in drytetrahydrofuran (50 ml) was added over 5 minutes. The mixture wasstirred in ice for 30 minutes, and methoxylamine hydrochloride (3.34 g,40.0 mmol) and triethylamine (4.06 g, 40.2 mmol) were added. The mixturewas stirred at room temperature for 24 hours, diluted with diethyletherand washed with water, twice with 10% hydrochloric acid solution,saturated sodium bicarbonate solution and brine. The solution was dried(MgSO₄), and the solvent was removed under vacuum to leave an oil (7.88g). Purification by flash chromatography (230–400 mesh silica gel; 40%ethyl acetate in hexane) gave the title compound (6b) as an oil (6.25g).

NMR (CDCl₃, TMS) δ0.899–0.969 (m, 3H, propyl CH₃), 1.62–1.83 (m, 2H,propyl N—C—CH₂), 2.849–3.074 (m, 4H), 3.774 (s, 3, O—CH₃). 3.623–3.880(m, 1.5H), 4.089–4.154 (m, 0.5H), 4.303–4.398 (m, 1H), 7.121–7.382 (m,4H), 7.794 & 7.858 (two s, 1H, NH).

[α]_(D)=−29° (25° C., CHCl₃, c=1.0139).

Preparation of(R)-5-N-(N-Propyltrifluoromethylacetamido)-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(7b)

A solution of(R)-N-Propyl-N-[3-(1-(N-methoxyaminocarbonyl)-1,2,3,4-tetrahydroquinolinyl)]trifluoromethylacetamide(6b, 5.92 g, 16.5 mmol) in chloroform (80 ml) was degassed with argonand heated to hear reflux on the steam bath.Bis(trifluoroacetoxy)iodobenzene (8.50 g, 19.8 mmol was addedportionwise. The reaction was exothermic. After the addition wascomplete, the solution was stirred at reflux for 5 minutes. The reactionmixture was cooled, diluted with pentane, and washed twice withsaturated sodium bicarbonate solution and once with brine. The solutionwas dried (MgSO₄), and the solvent was removed under vacuum to leave anoil (9.2 g). Purification by flash chromatography (230–400 mesh silicagel; 30% ethyl acetate in hexane) gave the title compound (7b) as anamber oil (3.75 g, 61% yield).

NMR (CDCl₃, TMS) δ0.918–0.967 (m, 3H, propyl CH₃), 1.60–1.87 (m, 2H,propyl N—C—CH₂), 2.91–3.08 (m, 1H), 3.16–3.42 (m, 2H), 3.63–3.79 (m,1H), 4.089 & 4.101 (two s, 3H, O—CH₃), 3.97–4.26 (m, 2.6H), 4.42–4.56(m, 0.4H), 6.884 –7.097 (m, 4H).

Preparation of(R)-5-Propylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(8b)

A solution of(R)-5-N-(N-Propyltrifluoromethylacetamido)-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(7b, 3.50 g, 9.79 mmol) in methanol (30 ml) and water (5 ml) was cooledin ice and potassium hydroxide (45.6% in water, 1.0 ml, 11.9 mmol) wasadded. The mixture was stirred at 0° C. for 1 hour and at roomtemperature for 18 hours. The solvent was concentrated under vacuum, andthe residue was partitioned between water and diethylether. The aqueouslayer was saturated with sodium chloride and extracted again withdiethylether. The combined organic extract was dried (MgSO₄), and thesolvent was removed under vacuum to leave an oil (2.43 g). Purificationby flash chromatography (230–400 mesh silica gel; ethyl acetate to 20%tetrahydrofuran in ethyl acetate) gave the title compound (8b) as asolid (1.79 g, 69% yield).

NMR (CDCl₃, TMS) δ0.927 (t, j=7.4 Hz, 3H, propyl CH₃), 1.112 (br. s, 1H,NH), 1.507 (sextet, j=7.3 Hz, 2H, propy N—C—CH₂), 2.629–2.804 (m, 3H),3.062 (dd, j=4.2 & 16.0 Hz, 1H), 3.291 (heptet, j=4.0 Hz, 1H, N—CH),3.557 (dd, j=7.7 & 12.2 Hz, 1H), 4.066–4.156 (m, 1H), 4.088 (s, 3H,O—CH₃), 6.887 (d, j=7.4 Hz, 1H), 6.961 (d, j=7.3 Hz, 1H), 7.036 (t,j=7.5 Hz, 1H).

A sample was dissolved in diethylether and excess ethereal hydrochloricacid was added. The precipitate was filtered, washed well withdiethylether, and crystallized from methanol/diethylether to give thehydrochloride salt of the title compound (8b) as a yellow solid (m.p.229 ° C. dec.).

[α]_(D)=−31° (25° C., CH₃OH, c=1.1099).

EXAMPLE 4(R)-5-Dipropylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(9b)

Following the procedure of Example 3, a mixture of(R)-5-Propylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(8b, 0.93 g, 3.56 mmol), 1-iodopropane (3.05 g, 17.9 mmol), andpotassium carbonate (1.97 g, 14.3 mmol) in acetonitrile (25 ml) washeated at reflux under nitrogen for 17 hours. 1-Iodopropane (3.05 g,17.9 mmol) was again added, and the mixture was refluxed for anadditional 5 hours. The solvent was removed under vacuum, and themixture was diluted with water and extracted twice with diethylether.The organic extract was washed with brine and dried (MgSO₄). The solventwas removed under vacuum to leave an amber oil. Purification by flashchromatography (230–400 mesh silica gel; 10–25% ethyl acetate in hexane)gave the title compound (9b) as an amber oil (0.87 g, 90% yield).

NMR (CDCl₃, TMS) δ0.894 (t, j=7.3 Hz, 6H, propyl CH₃), 1.456 (sextet,j=7.3 Hz, 4H, propyl N—C—CH₂), 2.524 (m, 8 lines, 4H, propyl N—CH₂),2.823–2.975 (m, 2H)3.277 (heptet, J=5.1 Hz, 1H), 3.435 (t, j=11.4 hz,1H), 4.076 (s, 3H, O—CH₃), 4.168 (dd, j=4.1 & 11.5 Hz, 1H), 6.883 (d,j=7.6 Hz, 1H), 6.942 (d, j=7.5 Hz, 1H), 7.021 (t, j=7.6 Hz, 1H).

The compound was dissolved in diethylether, and excess etherealhydrochloric acid was added. The precipitate was filtered, washed withdiethylether, and crystallized from methanol/diethylether to give thehydrochloride salt of the title compound (9b) as an off-white solid(1.12 g, m.p. 175–176° C).

[α]_(D)=−13° (25° C., CH₃OH, c=1.0682).

EXAMPLE 5(R)-5-Methylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(8a) (Scheme 2: Alternative Method of Example 1) Preparation of(R)-2-(Methoxycarbonylamino)-3-phenylpropanoic acid (2)

A solution of D-phenylalanine (25.00 g, 0.151 mol) and sodium hydroxide(6.05 g, 0.151 mol) in water (170 ml) and tetrahydrofuran (225 ml) wascooled to −15° C., and a solution of methyl chloroformate (18.6 g, 0.197mol) in tetrahydrofuran (50 ml) was added dropwise. When the additionwas ˜half complete, a solution of sodium hydroxide (9.10 g, 0.227 mol)in water (20 ml) was also added dropwise. When the additons werecomplete, the mixture was stirred at room temperature for an additonal 2hours and acidified with 10% hydrochloric acid. The acid was extractedtwice with diethylether, and the extracts were washed with brine anddried (MgSO₄). The solvent was removed under vacuum to leave a clear oil(38.38 g).

HPLC 6.01 min (78.9%), 7.32 min (5.0%), 8.29 min (10.8%), 8.42 min(0.5%), 9.95 min (1.2%), 10.27 min (2.8%), 11.92 min (0.7%).

Preparation of(R)-N-Methoxy-2-(methoxycarbonylamino)-3-phenylpropanamide (3)

A solution of sodium carbonate (10.20 g, 96.2 mmol) in water (170 ml)was added to a solution of the acid (˜0.148 mol) in methylene chloride.Methoxylamine hydrochloride (14.2 g, 0.170 mol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (31.21 g, 0.163 mol) wereadded, and the mixture was stirred at room temperature for 22 hours. Themixture was diluted with tetrahydrofuran (to dissolve the precipitate)and the layers were seprated. The aqueous layer was extracted with 1:1tetrahydrofuran/diethylether, and the combined organic extracts werewashed with 10% hydrochloric acid solution and saturated sodiumbicarbonate solution, and the solution was dried (MgSO₄). The solventwas removed under vacuum to leave a white solid (34.2 g).Crystallization from ethyl acetate gave colorless crystals (22.6 g, m.p.154°–155° C.).

[α]_(D)=+5° (25° C., CH₃OH, 1.0450).

Preparation of Methyl(R)-N-(1,2,3,4-Tetrahydro-1-methoxy-2-oxo-3-quinolinyl)carbamate (4)

A suspension of(R)-N-Methoxy-2-(methoxycarbonylamino)-3-phenylpropanamide (11.25 g,44.6 mmol) in 1,2-dichloroethane (170 ml) was cooled in ice andtrifluoroacetic acid (9.25 ml, 13.7 g, 0.120 mol) was added.Bis(trifluoroacetoxy)iodobenzene (19.78 g, 0.046 mol) was addedportionwise over 10 min at 0° C., and the mixture was stirred at thesame temperature for 1 hour. The mixture was washed with 10% sodiumcarbonate solution and dried (MgSO₄). The solvent was removed undervacuum to leave an amber oil (19.58 g). Purification by flashchromatography (230–400 mesh silica gel, 40–50% ethyl acetate in hexane)gave an amber oil which solidified (9.45 g, 85% yield). A sample (1.5 g)was crystallized from ethyl acetate/hexane to give white crystals (1.36g, m.p. 117°–119° C.).

[α]_(D)=+34° (25° C., CH₃OH, 0.9279).

Preparation of (R)-3-Methylamino-1,2,3,4-tetrahydroquinoline maleate (5)

A solution of(R)-N-(1,2,3,4-Tetrahydro-1-methoxy-2-oxo-3-quinolinyl)carbamate (7.27g, 29.1 mmol) in dry tetrahydrofuran (100 ml) was cooled in a water bath(˜10° C.), and boron dimethylsulfide complex (10.0M, 17.5 ml, 6.0 eq)was added. The mixture was stirred in the water bath for 1 hour and atroom temperature for 1.5 hours. The mixture was heated at reflux on thesteam bath for 30 hours, cooled in ice, and 10% hydrochloric acid (40ml) was added dropwize. The mixture was refluxed on the steam bath for1.5 hours, cooled in ice, and basified with 45% potassium hydroxide. Themixture was extracted twice with diethylether, and the combined extractswere washed with brine and dried (MgSO₄). The solvent was removed undervacuum to leave a clear oil 4.89 g. The compound (0.029 mol) wascombined with maleic acid (3.38 g, 0.029 mol), and the mixture wascrystallized from methanonal/diethylether to give the title compound asoff-white crystals (5.77 g, 71% yield, VPC shows 5.451 min (100%)). Asample (1.0 g) was recrystallized from methanol/diethylether to give acolorless solid (m.p. 173.5°–175° C.).

Preparation of (R)-Methyl-(1,2,3,4-tetrahydro-3-quinolinyl) carbamicacid, phenylmethyl ester (6)

A solution of (R)-1,2,3,4-tetrahydro-N-methyl-3-quinolinamine (6.00 g,31.5 mmol) and triethylamine (4.8 g, 47.4 mmol) in chloroform (200 ml)was cooled to −30° C., and a solution of benzyl chloroformate (5.68 g,95% pure, 31.6 mmol) in chloroform (50 ml) was added dropwise. Themixture was stirred at −30° to 0° C. for 2 hours, and 10% sodiumcarbonate solution (100 ml) was added, the mixture was stirred at roomtemperature for 1 hour, diluted with pentane and diethylether, and thelayers were separated. The aqueous layer was extracted withdiethylether, and the combined organic extracts were washed with brineand dried (MgSO₄). The solvent was removed under vacuum to leave an oil(10.91 g). Purification by flash chromatography (230–400 mesh silicagel; 4:1 hexane/ethyl acetate) gave an oil (7.53 g, 81% yield). A sample(0.57 g) was crystallized from ethyl acetate/hexane to give whitecrystals (0.42 g, m.p. 78.5–80° C.). [α]_(D)=−47° (25° C., CH₃OH,0.8166).

Preparation of(R)-Methyl-[1,2,3,4-tetrahydro-1-[(methoxyamino)carbonyl]-3-quinolinyl]carbamicacid, phenylmethyl ester (7)

A solution of (R)-methyl-(1,2,3,4-tetrahydro-3-quinolinyl)carbamic acid,phenylmethyl ester (3.81 g, 12.86 mmol) and triethylamine (3.9 g, 39mmol) in dry tetrahydrofuran (50 ml) was rapidly added with stirring toa solution of phosgene (1.93 M in toluene) in tetrahydrofuran (100 ml)at 0° C. The cold bath was removed, and the mixture was stirred for 1.25hours. Methoxylamine (2.15 g, 25.7 mmol) and triethylamine (7.9 g, 78mmol) were added, and the mixture was stirred at room temperature for 3days. The mixture was diluted with diethylether and washed with waterand brine. The solution was dried (MgSO₄), and the solvent was removedunder vacuum to leave an oil (5.13 g, >100%) which was sufficiently purefor the next step. A sample (0.91 g) was purified via flashchromatography (230–400 mesh silica gel; 50% ethyl acetate/hexane) togive an oil. [α]_(D)=+38° (25° C., CH₃OH, 0.9805). ass spec. m+ at m/z369. Strongest peaks at m/z 43, 65, 91, 118, 130, 158, 173, 204.

Exact mass calcd. for C₂₀H₂₃N₃O₄: 369.1688. Found: 369.1682.

Preparation ofMethyl-(1,2,5,6-tetrahydro-1-methoxy-2-oxo-4H-imidazo[4,5,1-ij]quinolinyl-5-yl)carbamicacid, phenylmethyl ester (8)

A solution of(R)-Methyl-[1,2,3,4-tetrahydro-1-[(methoxyamino)carbonyl]-3-quinolinyl]carbamicacid, phenylmethyl ester (7.26 g, 19.7 mmol) in chloroform (150 ml) wasdegassed with argon, and the mixture was cooled to −5° C. in an ice-saltbath Bis(trifluoroacetoxy)iodobenzene (10.14 g, 23.6 mmol) was added,and the mixture was stirred at −5 to 0° for 4 hours and at roomtemperature for 2 hours and was stored at −15° C. overnight. The mixturewas washed with 10% sodium carbonate solution, and the aqueous washingswere back extracted with diethylether. The combined organics were dried(MgSO₄), and the solvent was removed under vacuum to leave a brown oil(10.7 g). Purification by flash chromatography (230–400 mesh silica gel,50% ethyl acetate in hexane) gave an amber oil which slowly solidified(5.67 g, 78%). A sample (0.54 g) was crystallized from ethylacetate/hexane to give off-white crystals (0.41 g, m.p. 105–106.5° C.[α]_(D)=+44° (25° C., CH₃OH, 0.7311).

Preparation of(R)-5,6-Dihydro-1-methoxy-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2-one(8a)

Selective Hydrogenation:

A mixture ofmethyl-(1,2,5,6-tetrahydro-1-methoxy-2-oxo-4H-imidazo[4,5,1-ij]quinolinyl-5-yl)carbamicacid phenylmethyl ester (1.48 g, 4.03 mmol) and 10% palladium on carbon(0.25 g) in absolute ethanol (100 ml) was stirred under one atmosphereof hydrogen. After taking up one equivalent of hydrogen, the mixture wasfiltered through celite, and the solvent was removed under vacuum toleave an oil.

Preparation of(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one,monohydrochloride

Exhaustive Hydrogenation:

A mixture ofmethyl-(1,2,5,6-tetrahydro-1-methoxy-2-oxo-4H-imidazo[4,5,1-ij]quinolinyl-5-yl)carbamicacid phenylmethyl ester (1.48 g, 4.03 mmol) and 20% palladium hydroxideon carbon (0.50 g) in absolute ethanol (100 ml) was shaken in aapparatus with an initial hydrogen pressure of 50 psi for 17 hours. Themixture was filtered through celite, and the solvent was removed undervacuum to leave an oil (0.86 g). The compound was dissoved in methanoland excess ethereal hydrochloric acid was added. The mixture was dilutedwith diethylether, and the precipitate was filtered and crystallizedfrom methanol/diethylether to give an off-white solid (0.61 g, 63%yield, m.p. 310–311° C.). [α]_(D)=−30° (25° C., CH₃OH, 1.0182).

1. A compound of the following structural formula:

and pharmaceutically acceptable salts thereof.